Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([OH:26])=O)[C:8]=3[NH:9][C:10]=2[CH:11]=1.Cl.CN.Cl.[CH3:31][N:32](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:13]=[C:12]([C:24]([NH:32][CH3:31])=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-c2cc(C(=O)O)c3[nH]c4cc(OC)ccc4c3n2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CNC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylic acid (Example 127D) (60 mg, 0.17 mmol), methylamine hydrochloride (19 mg, 0.28 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (43 mg, 0.22 mmol), and 1-hydroxybenzotriazole hydrate (30 mg, 0.22 mmol) in a vial was flushed with nitrogen and dimethylformamide (0.5 mL) followed by triethylamine (38 μL, 0.28 mmol) were added. After stirring overnight, the reaction was diluted with methanol and the product was isolated by preparative HPLC (100×30 mm Luna C18 column, gradient elution starting with A:B=10:90 and ending with A:B=70:30 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents. This gave 7-methoxy-2-(4-methoxyphenyl)-N-methyl-5H-pyrido[3,2-b]indole-4-carboxamide (41 mg, 63% yield) as a yellow solid. MS (ESI) m/z 362.3 (M+H). 1H NMR (MeOD) δ ppm 8.26 (1H, d, J=8.55 Hz), 8.00-8.04 (2H, m), 7.98 (1H, s), 7.17 (1H, d, J=2.14 Hz), 7.07-7.10 (2H, m), 6.92 (1H, dd, J=8.70, 2.29 Hz), 3.94 (3H, s), 3.89 (3H, s), 3.06 (3H, s).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=1[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:33](=[O:34])[CH2:32][C:25]2[CH:26]=[C:27]([F:31])[CH:28]=[C:29]([F:30])[C:24]=2[F:23])[CH2:4][CH2:5]3)=[CH:13]1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2F)c2c(N)ncnc21

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (2,3,5-trifluorophenyl)acetic acid, HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. LCMS (62-A1-ON) indicated partial conversion, with a mixture of starting material, desired product and bis-acylated material, so the reaction mixture was poured into water (10 mL), and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water (10 mL), and dried at the pump for an hour. The beige solid was adsorbed onto silica, and purified by flash chromatography (0-10% methanol in DCM, 12-g column) to afford a pale yellow solid which showed presence of bis-acylated material. The product was adsorbed onto silica and purified by flash chromatography (100% EtOAc-10% MeOH in EtOAc, then 10% MeOH in DCM, 12-g column) to afford 7-methyl-5-{1-[(2,3,5-trifluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (102 mg, 52.6% yield) as a white solid. LC-MS (ES) m/z=438 [M+H]+. 1H NMR (DMSO-d6, 400 MHz): δ 3.28 (t, J=8.3 Hz, 2H), 3.74 (s, 3H), 4.04 (s, 2H), 4.29 (t, J=8.5 Hz, 2H), 6.08 (br. s., 2H), 7.10-7.17 (m, 1H), 7.20-7.28 (m, 2H), 7.34 (s, 1H), 7.42-7.53 (m, 1H), 8.08 (d, J=8.1 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=1)=[O:30]>>[O:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[CH:35]=[C:31]1[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:21][CH:20]=1)=[O:30]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCO)c1cc2ccccc2o1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2cc3ccccc3o2)cc1
Yield: 53 %

Procedure:
The product of Example 2 (0.442 g, 1.37 mmol) was coupled to N-(3hydroxypropyl)-1-benzofuran-2-carboxamide (0.3 g, 1.37 mmol) using the procedure of Example 3 to provide 0.37 g (53% yield) of an off white powder. MP 184-186° C.; 1H NMR (DMSO-d6): δ 1.9 (s, CH3), 2.04 (t, CH2), 3.16 (s, CH3), 3.46 (q, CH2), 4.0 (t, CH2), 7.01 (d, 2 Ar H) 7.30-7.78 (m, 10 Ar H), 8.56 (t, NH), 12.4 (br s, OH). Electrospray Mass Spec: m/z 523.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH2:25].[BH4-].[Na+]>>[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:17]=[C:2]([F:1])[C:3]([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=2)=[C:14]([F:20])[CH:15]=1
Reactant: NC(=O)c1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 80.4 %

Procedure:
Using a method similar to Example 710, Step 4, using 6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (278 mg, 1.00 mmol), 3,3-dimethylbutylamine (105 mg, 1.20 mmol), and NaBH4 (57 mg, 1.50 mmol) gave the title compound (292 mg) as a white solid. Mass spectrum (ion spray): m/z=364 (M+1); 1H NMR (DMSO-d6): 8.54 (s, 1H), 8.30 (d, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 7.29 (d, 1H), 7.22 (d, 2H), 3.71 (s, 2H), 2.49 (t, 2H), 1.36 (m, 2H), 0.86 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].C[O:9][C:10](=O)/[CH:11]=[C:12](/[O:15][CH3:16])\[CH2:13]Cl.COC(=O)C/C=C/OCCl>O>[CH3:16][O:15][C:12]1[CH2:13][N:1]([CH2:2][C:3]([OH:5])=[O:4])[C:10](=[O:9])[CH:11]=1
Reactant: COC(=O)/C=C(\CCl)OC
Reactant: NCC(=O)O
Agent: COC(=O)C/C=C/OCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1=CC(=O)N(CC(=O)O)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 304.6 %

Procedure:
30 g (400 mmol) of glycine was suspended in 60 ml of H2O and heated to 70° C. 10M of NaOH was added with an autotitrator up to pH 8.5. Then, 22.4 g (136 mmol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester was added at 70° to 75° C. The pH was kept constant at 8.5 by adding 10M of NaOH. After 1 hour, another 22.4 g (136 mmol) of 4-chloro-3-methoxy-but-2E-enoic acid methyl ester was added, and, after another hour, 22.4 g (136 mmol) of 4-chloromethoxy-but-3E-enoic acid methyl ester again was added. After the final addition, the reaction mixture was stirred for another 3.5 hours at 70° to 70° C. The consumption of 10M of NaOH was then 80.3 ml, which corresponded to 2 equivalents relative to the glycine used. The reaction mixture was cooled to room temperature and diluted with 40 ml of H2O. Then, the reaction mixture was adjusted to pH 1 with concentrated HCl. The product precipitated after a short time, was filtered off and washed with saturated NaCl solution. After drying, 70.9 g of product was obtained. 3.41 g of product was obtained from the mother liquor. The total yield was 84 percent. The crude product was recrystallized from isopropanol: 68 g was recrystallized from 450 ml of isopropanol. 47 g of product, which corresponded to an 87 percent yield, was obtained. The product contained less than 0.01 percent of Cl31. Other data for the product was:
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:19]CCC(C1C=CC=CC=1)=O.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: CCCC(=O)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(C)c1
Yield: 84 %

Procedure:
Compound 9e was synthesized by a procedure similar to that described for 9a using commercially available 3-methylpropiophenone (8e, 5.0 g, 0.033 mol), TBDMSOTf (8.5 mL, 36.1 mmol), and Et3N (7.5 mL) in CH2Cl2 (50 mL). After purification by column chromatography on silica gel, 7.45 g (84%) of 9e was isolated as colorless oil: 1H NMR (CDCl3) δ 7.31-7.24 (m, 2H), 7.23-7.17 (m, 1H), 7.10-7.05 (m, 1H), 5.22 (q, 1H, J=6.9 Hz), 2.37 (s, 3H), 1.76 (d, 3H, J=6.9 Hz), 1.03 (s, 9H), −0.03 (s, 6H); 13C NMR (CDCl3) δ 150.7, 140.1, 137.7, 128.4, 127.9, 126.8, 123.2, 105.9, 26.3, 21.8, 18.7, 12.1, −3.6. C16H26OSi.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[CH3:23]S(C)=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.5 h

Procedure:
6.4 grams (0.02 mole) of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate is dissolved in 100 ml. of dimethyl sulfoxide (DMSO) and added to a slurry of 0.48 g. (0.02 mole) of sodium hydride in approximately 30 ml. of DMSO. The mixture is stirred for 30 minutes before 2.84 g. (0.02 mole) of methyl iodide is added. Stirring is continued for 15 minutes. The reaction mixture is then poured into water, and the precipitate filtered off and recrystallized from 2-propanol to yield ethyl 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate, m.p. 88-90° C.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH:5]=[CH2:6].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=[O:19]>C(OCC)C>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]([OH:19])[CH2:6][CH:5]=[CH2:4]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C=CCBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.28 g of magnesium are treated with an iodine crystal and covered with absolute diethyl ether. The reaction is started by the addition of 2 g of allyl bromide. A mixture of 19.78 g of allyl bromide and 15.62 g of 2-naphthaldehyde in absolute diethyl ether is then added dropwise to maintain the mixture at reflux. After the addition is completed, the mixture is left to stir at room temperature overnight. The mixture is poured into an ice - 2 N hydrochloric acid solution and extracted three times with ether. The ether extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to yield 1-(2-naphthyl)-3-buten-1-ol which can be used without further purification for the reaction with cyclopropane carboxylic acid chloride in the process of Example 2. The resulting product is cyclopropane carboxylic acid 1-(2-naphthyl)-3-butenyl ester, m.p. 35°-39° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)CCl)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of 2,4-dimethoxybenzylamine (1.50 mL, 10.0 mmol) and triethylamine (2.00 mL, 14.3 mmol) in tetrahydrofuran (20 mL) at 0° C. was added chloroacetyl chloride (0.80 mL, 10 mmol). The reaction was then stirred at 0° C. for three hours. The crude reaction mixture was partitioned between ethyl acetate and water, and the organic layer dried over brine and magnesium sulfate, filtered, and evaporated in vacuo to yield 2.2074 g (91%) of N-(2,4-Dimethoxy-benzyl)-2-chloro-acetamide which was carried forward without purification. LCMS (Method E, ESI): RT=1.43 min, m+H=244.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][C:32]1[S:36][C:35]([CH:37]=[O:38])=[N:34][CH:33]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:37]([C:35]2[S:36][C:32]([CH2:31][O:30][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)=[CH:33][N:34]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (526 mg) in ethanol (6 mL) were added 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (402 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43.7 mg) and triethylamine (88 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (366 mg, yield 43%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[N:12]=[C:11]2[C:13](=O)[CH2:14][CH2:15][O:16][C:10]2=[CH:9][CH:8]=1.[NH2:24]O.Cl.C[C:28]([O-:30])=O.[K+]>CO>[CH3:28][O:30][N:24]=[C:13]1[C:11]2=[N:12][C:7]([C:6]3[S:5][C:4]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=[C:10]2[O:16][CH2:15][CH2:14]1
Reactant: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCO2
Reactant: NO
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C1CCOc2ccc(-c3sc(-c4cccnc4)nc3C)nc21
Yield: 76.9 %

Procedure:
6-[4-methyl-2-(3-pyridyl)thiazol-5-yl]-2,3-dihydropyrano[3,2-b]pyridin-4-one (100 mg, 0.31 mmol), compound H2N—OH.HCl (51 mg, 0.62 mmol) and KOAc (61 mg, 0.62 mmol) were suspended in methanol (3 mL) under N2. The reaction mixture was refluxed for 18 hours and purified by chromatography on silica (Ethyl acetate) to get the pure compound as yellow solid (84 mg, 78%). 1H NMR (400 Mz, CDCl3): 2.68 (s, 3H); 2.97 (t, 2H); 4.00 (s, 3H); 4.28 (t, 2H); 7.55-7.46 (m, 2H); 7.72-7.69 (m, 1H); 8.231-8.29 (m, 2H); 8.66-8.65 (m, 1H); 9.13 (s, 1H). Mpt 148-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:7]([C:6]1[CH:9]=[C:2]([O:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (84.0 g) and ethyl 4-bromobutanoate (86 ml) in dry dimethylformamide (500 ml) blanketed under dry nitrogen was added potassium carbonate (76.0 g). The reaction mixture was heated to 100° C. for 1 hour. This mixture was cooled, and the solvent removed by evaporation to give a drak brown syrup. This residue was partitioned between ethyl acetate and saturated sodium carbonate (500 ml each). The organic layer was washed with additional saturated sodium carbonate (3×500 ml), and with brine (2×500 ml), dried, filtered and evaporated to give a drak brown syrup. Kugelrohr distillation (180° C., 0.2 mm) afforded ethyl 4-((3-formyl-4-nitrophenyl)oxy)butanoate (95 g) as a bright yellow syrup which slowly darkened upon standing.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH:6]([OH:10])[CH2:7][CH:8]=[CH2:9].[H-].[Na+].[CH3:15]I.O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:15][O:10][CH:6]([CH2:5][CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[CH2:7][CH:8]=[CH2:9]
Reactant: CI
Reactant: C=CCC(O)CCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCC(CCC(OC)OC)OC
Reaction time: 0.17 h

Procedure:
7,7-Dimethoxyhept-1-en-4-ol obtained in Preparation Example 59-(1) (6.16 g) was dissolved in 1-methyl-2-pyrrolidinone (60 mL), and the solution was cooled in an ice bath under a nitrogen atmosphere. Then, sodium hydride (60%, 2.12 g) was added, followed by stirring for 10 minutes. Methyl iodide (6.61 g, 2.28 g/cm3) was further added and the mixture was further stirred for two hours and 10 minutes. After slowly adding water, ethyl acetate was added, followed by further stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (5.83 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[F:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:20][N:19]=2)=[O:22])[CH2:63][CH2:62]1
Reactant: Fc1ccc(NC2CCNCC2)c(F)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccc(F)cc2F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 16.5 %

Procedure:
DIPEA (232 mg, 1.8 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (148 mg, 0.6 mmol) in DMF (2 mL) followed by HOBt (95 mg, 0.7 mmol) and EDCI.HCl (137 mg, 0.7 mmol. After 2 minutes (2,4-difluoro-phenyl)-piperidin-4-yl-amine dihydrochloride (prepared by the method used for the synthesis of Intermediate 3) (150 mg, 0.6 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer thus collected was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeoH in CHCl3 as eluent) to afford 43 mg (16.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,4-difluoro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440.18, 94.52%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.4 (m, 4H), 7.0 (m, 1H), 6.9 (m, 2H), 5.0 (m, 1H), 4.4 (m, 1H), 4.2 (m, 2H), 3.5 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:13])[CH:11]=[CH2:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:20]1)C[C:15]2=O>ClCCl.COC(OC)(C)C>[CH:11]([CH:10]1[O:13][C:14]([CH3:20])([CH3:15])[O:1][CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9]1)=[CH2:12]
Reactant: C=CC(O)CC(O)CC(=O)OCC
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: C=CC1CC(CC(=O)OCC)OC(C)(C)O1
Reaction time: 8 h

Procedure:
The crude β,δ-dihydroxy-6-heptenoic acid, ethyl ester from the previous step was dissolved in a mixture of 30 mL of dichloromethane and 10 mL of 2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and the mixture was stirred overnight. Concentration of the reaction mixture and flash chromatography of the residue yielded 1.1 g of 6-ethenyl-2,2-dimethyl-l,3-dioxane-4-acetic acid, ethyl ester.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6]O.ClCCl.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.S([O-])([O-])(=O)=[O:25].[Mg+2]>CC(C)=O>[CH3:14][C:13]1([CH3:18])[O:8][CH:2]([CH:3]([OH:25])[CH2:4][CH2:5][CH3:6])[CH2:1][O:9]1
Reactant: O=S(=O)([O-])[O-]
Reactant: OCCCCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCC(O)C1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1,2,6-hexanetriol (10.0 g, 74.6 mmol) in acetone (50 ml) was added dichloromethane (50 ml), p-toluene sulphonic acid (1 mol %, catalyst) and anhydrous magnesium sulphate (50 g). The mixture was allowed to stir at ambient temperature for 24 hours. The MgSO4 was then removed via filtration and the acetone/dichloromethane solution washed with saturated sodium bicarbonate solution (1×30 ml) and water (2×30 ml). The organic solution was then dried over anhydrous MgSO4, filtered and solvent removed in vacuo, to yield the product as a colourless liquid. Yield=13.0 g (79%).
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=CC=2)[C:9]2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:27]C1C=CC(C(=O)C)=CC=1>C1COCC1.CCCCCC>[Br:27][C:5]1[CH:6]=[CH:7][C:2]([C:8]([CH3:15])=[CH2:9])=[CH:3][CH:4]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a slurry of triphenylmethylphosphonium bromide (71.4 g, 200 mmole), in 500 ml dry THF at 0° C., were slowly added dropwise 135 ml (200 mmole) 1.44 M n-butyllithium in hexane. The mixture was stirred 30 minutes at 0° C., and a solution of 39.8 g (200 mmole) p-bromoacetophenone, in 100 ml dry THF, was slowly added dropwise. The mixture was allowed to warm slowly to ambient temperature, whereafter stirring was continued overnight. The stirred mixture was next filtered and the solvent removed by careful distillation at atmospheric pressure, the resulting residue was diluted with hexane, filtered, and the hexane removed by distillation. The remaining material was distilled, using a water aspirator vacuum, to produce 23.2 g (58.3% yield) of p-bromo-α-methylstyrene, bp 95°-98° C.
Reaction SMILES: [N:1]([CH:4]([CH3:10])[CH2:5][CH2:6][C:7](O)=[O:8])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH:4]([CH3:10])[CH2:5][CH2:6][C:7]([Cl:13])=[O:8])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: CC(CCC(=O)O)N=[N+]=[N-]
Product: CC(CCC(=O)Cl)N=[N+]=[N-]
Yield: 75.1 %

Procedure:
A mixture of crude 4-azidopentanoic acid (8.0 g, 56 mmol) and thionyl chloride (10 g 84 mmol) was heated at 40°-45° C. for 1.5 h, followed by evaporation of excess thionylchloride in vacuo. The residual oil was distilled to give 6.8 g (75%) of the title compound, bp 60°-65° C./0.3 mm: 1Hmr (CDCl3) δ: 3.55 (1H, q, J=13 Hz), 3.03 (2H, t, J=13 Hz), 1.9 (2H, t, J=13 Hz and 1.3 ppm (3H, d, J=13 Hz); ir (neat) νmax : 2100, 1792 cm-1.